1. Field of the Invention
The compounds of this invention are analogues of natural prostaglandins.
Natural prostaglandins are alicyclic compounds related to prostanoic acid, the structure of which is: ##STR3## By convention, the carbon atoms of I are numbered sequentially from the carboxylic carbon atom. An important stereochemical feature of I is the trans-orientation of the sidechains C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20, an orientation common to all natural prostaglandins. In I, as elsewhere in this specification, solid lines (--) provide a reference plane (such as the cyclopentyl ring or the bonds among atoms C.sub.1 -C.sub.7 and C.sub.13 -C.sub.20); a dashed line (----) indicates projection of a covalent bond below such reference plane (alpha-configuration); while a wedged line ( ) represents direction above such plane (beta-configuration). Those conventions apply to all structural formula subsequently discussed in this specification. In some structures, however, a swung dash or serpentine line (.about.) denotes orientation of a covalent bond either above or below a plane of reference (indicated by the Greek letter xi in the nomenclature of such structures).
Natural prostaglandins have the general structure, ##STR4## in which: L and M may be ethylene or cis-vinylene radicals; and the cyclopentyl ring ##STR5## may be: ##STR6##
Formula II and all representations of the cyclopentyl moiety depict the nat-isomer, i.e., the C.sub.7 -C.sub.8 bond in the alpha-configuration and the C.sub.12 -C.sub.13 bond in the beta-configuration. In the ent-isomer (which does not occur in nature), the direction of the bonds at C.sub.7 -C.sub.8 and C.sub.12 -C.sub.13 is reversed.
Prostaglandins are classified according to the functional groups present in the five-membered ring and the presence of double bonds in the ring or chains. Prostaglandins of the A-class (PGA or prostaglandin A) are characterized by an oxo group at C.sub.9 and a double bond at C.sub.10 -C.sub.11 (.DELTA..sup.10,11); those of the B-class (PGB) have an oxo group at C.sub.9 and a double bond at C.sub.8 -C.sub.12 (.DELTA..sup.8,12); compounds of the C-class (PGC) contain an oxo group at C.sub.9 and a double bond at C.sub.11 -C.sub.12 (.DELTA..sup.11,12); members of the D-class (PGD) have an oxo group at C.sub.11 and an alpha-oriented hydroxy group at C.sub.9 ; prostaglandins of the E-class (PGE) have an oxo group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11 ; and members of the F.sub..alpha. -class (PGF.sub..alpha.) have an alpha-directed hydroxyl group at C.sub.9 and an alpha-oriented hydroxyl group at C.sub.11. Within each of the A, B, C, D, E, and F classes of prostaglandins are three subclassifications based upon the presence of double bonds in the side-chains at C.sub.5 -C.sub.6, C.sub.13 -C.sub.14, or C.sub.17 -C.sub.18. The presence of a trans-unsaturated bond only at C.sub.13 -C.sub.14 is indicated by the subscript numeral 1; thus, for example, PGE.sub.1 (or prostaglandin E.sub.1) denotes a prostaglandin of the E-type (oxo-group at C.sub.9 and an alpha-hydroxyl at C.sub.11) with a trans-double bond at C.sub.13 -C.sub.14. The presence of both a trans-double bond at C.sub.13 -C.sub.14 and a cis-double bond at C.sub.5 -C.sub.6 is denoted by the subscript numeral 2; for example, PGE.sub.2. Lastly, a trans-double bond at C.sub.13 -C.sub.14, a cis-double bond at C.sub.5 -C.sub.6 and a cis-double bond at C.sub.17 -C.sub.18 is indicated by the subscript numeral 3; for example, PGE.sub.3. The above notations apply to prostaglandins of the A, B, C, D, and F series as well; however, in the last, the alpha-orientation of the hydroxyl group at C.sub.9 is indicated by the subscript Greek letter .alpha. after the numerical subscript.
Nomenclature of prostaglandins and their analogues deserves note insofar as there are three current systems followed in the scientific and patent literature. One system for convenience referred to as the Nelson system, uses the trivial names of prostaglandins and designates analogues by modifications of the trivial names (see -- J. Med. Chem., 17; 911 [1974]). Another system follows the rules of the International Union of Pure and Applied Chemistry (IUPAC) and refers to prostaglandins and their analogues as derivatives of heptanoic acid. A third system employs a convention of Chemical Abstracts ("CA") that designates prostaglandins and derivatives thereof as derivatives of prostanoic acid. An example of each system is provided below for the following structure: ##STR7## In the Nelson system, III is designated prostaglandin F.sub.3.alpha. or PGF.sub.3.alpha. (shortened form); in the IUPAC system, 7-[3R,5S-dihydroxy-2R-(3S-hydroxy-1E,5Z-octadienyl)-cyclopent-1R-yl]-5Z-he ptenoic acid; in the CA system, (5Z,9.alpha.,11.alpha.,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien -1-oic acid.
It is important to note that in all natural prostaglandins there is a hydroxyl group at C.sub.15 oriented below the plane in which C.sub.15 is located. In the Cahn-Ingold-Prelog system of defining stereochemistry, that C.sub.15 hydroxyl group is in the S-configuration. Inversion of the orientation of the C.sub.15 hydroxyl group such that the group projects above the plane in which the C.sub.15 atom is located represents the R-configuration. The Cahn-Ingold-Prelog system is used to define stereochemistry of any asymmetric center outside of the carbocyclic ring in all three systems of nomenclature described above. In some literature, however, .alpha.,.beta. designations are used for such centers.
Isomerism of a double bond is designated in all three systems by use of conventional prefixes cis- or trans-, or their respective equivalents, Z or E (as suggested in J. Am. Chem. Soc., 59: 509 [1968]).
For details of other conventions utilized in nomenclature of prostaglandins, see: Neston, N. A., "Prostaglandin Nomenclature," J. Med. Chem., 17: 911 (1974).
Recent research indicates that prostaglandins appear ubiquitously in animal tissues and elicit biochemical and physiological effects in a variety of mammalian systems.
In the endocrine system, for example, experimental evidence indicates prostaglandins influence the hormone synthesis or release of hormones in the secretory glands. In rats, PGE.sub.1 and PGE.sub.2 increase the release of the growth hormone while PGA.sub.1 increases its snythesis. In sheep, PGE.sub.1 and PGF.sub.1.alpha. inhibit ovarian progesterone secretion. In a variety of mammals, PGF.sub.1.alpha. and PGF.sub.2.alpha. act as luteolytic factors. In mice, PGE.sub.1, PGE.sub.2, PGF.sub.1.alpha. and PGF.sub.1.beta. increase thyroid activity. In hypophysectomized rats, PGE.sub.1, PGE.sub.2 and PGF.sub.1.alpha. stimulate stereoidogenesis in the adrenal glands.
In the mammalian male reproductive system, PGE.sub.1 contracts the smooth muscle of the vas deferens. In the female reproductive system, PGE and PGF.sub..alpha. compounds contract uterine smooth muscle. In general, PGE, PGB and PGA compounds relax in vitro human uterine muscle strips, while those of the PGF.sub..alpha. class contract such isolated preparations. PGE compounds, in general, promote fertility in the female reproductive system while PGF.sub.2.alpha. has contragestational effects. PGF.sub.2.alpha. also appears to be involved in the mechanism of menstruation. In general, PGE.sub.2 produces potent oxytocic effects in inducing labor, while PGF.sub.2.alpha. induces spontaneous abortions in early pregnancy.
PGF.sub..alpha. and PGE compounds have been isolated from a variety of nervous tissues. PGE.sub.1 retards whereas PGF.sub.2.alpha. facilitates transmission along motor pathways in the central nervous system. PGE.sub.1 and PGE.sub.2 reportedly inhibit transmitter release from adrenergic nerve endings in the guinea pig.
Prostaglandins stimulate contraction of gastrointestinal smooth muscle in vivo and in vitro. In dogs, PGA.sub.1, PGE.sub.1, and PGE.sub.2 inhibit gastric secretion. PGA.sub.1 exhibits similar activity in man. Natural prostaglandins and some of their analogues also protect gastric mucosa from ulceration induced by nonsteroidal antiinflammatory agents.
In most mammalian respiratory tracts, PGE and PGF compounds affect in vitro preparations of tracheal smooth muscle. Specifically, PGE.sub.1 and PGE.sub.2 relax while PGF.sub.2.alpha. contracts such smooth muscle. The human lung normally contains PGE and PGF compounds; consequently, some cases of bronchial asthma may involve an imbalance in the production or metabolism of those compounds.
Prostaglandins are involved in certain hematic mechanisms in mammals. PGE.sub.1, for example, inhibits aggregation of blood platelets in vitro.
In a variety of mammalian cardiovascular system, compounds of the PGE and PGA classes are vasodilators whereas those of the PGF.sub..alpha. class are vasoconstrictors, by virtue of their action on vascular smooth muscle.
Prostaglandins naturally appear in the kidney and reverse experimental and clinical renoprival hypertension.
The prostaglandins and their analogues have broad clinical implications. In obstetrics and gynecology, they may find use in fertility control, treatment of menstrual disorders, the induction of labor, and the correction of hormone disorders. In gastroenterology, they may help treat or prevent peptic ulcers and various disorders involving motility, secretion, and absorption in the gastrointestinal tract. They may, in the respiratory area, prove beneficial in the therapy of bronchial asthma and other diseases involving bronchoconstriction. In hematology, they may display utility as anti-clotting agents in diseases such as venous thrombosis, thrombotic coronary occlusion and other diseases involving thrombi. For circulatory diseases, they have therapeutic utility in hypertension, peripheral vasopathies and cardiac disorders.
The following references include a more complete review of the chemical, physiological and pharmacological aspects of the prostaglandins: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180: 1-568 (1971); Higgins and Braunwald, J. Am. Med. Assn., 53: 92-112 (1972); Osterling, Marozowich, and Roseman, J. Phar. Sci., 61: 1861-1895 (1972); and Nakano, Resident and Staff Phys., 19: 92, 94-99, and 102-106 (1973).